PAH Treatments Fail to Benefit Patients with PH due to Left Heart Disease, Study Suggests

Off-label use of pulmonary arterial hypertension (PAH) medications to treat patients with pulmonary hypertension caused by left heart disease (PH-LHD) is common, despite a lack of supporting clinical data. Now, a systematic review and pooled analysis of several clinical trials suggests that such practice does not benefit PH-LHD patients and advises against its continued use.

Left heart disease, marked by the left ventricle either failing to contract (pump) or rest (filling with blood to pump) normally, is the most common cause of PH-LHD. Currently, no approved therapies exist for these patients, and current guidelines recommend treating the underlying heart disorder.

The prevalence of off-label PAH prescriptions given may result from the misconception that PAH and PH-LHD share similar disease mechanisms, the researchers noted.

“However, the lack of clinical benefit in most trials of PAH therapy in PH-LHD, and the presence of adverse clinical outcomes in certain others, make such practice concerning,” the researchers wrote.

“PH-LHD, compared to PAH, is pathophysiologically distinct,” their study notes, “as PH-LHD is predominantly due to passive transmission of elevated left atrial pressure into the pulmonary artery, although pulmonary vascular remodelling can develop in PH-LHD.”

Researchers with the department of cardiology at Royal Prince Alfred Hospital, in Australia, set out to collect all available evidence addressing the clinical benefits of treating PH-LHD with PAH medications.

They extensively reviewed published literature and identified 10 randomized, placebo-controlled trials, which they then submitted to a comprehensive pooled analysis.

Altogether, the trials included 439 PH-LHD patients treated with a vasodilator indicated to treat PAH, and 338 patients given placebo as controls. Patients were followed for a minimum of 12 weeks and a maximum of 52 weeks, depending on the trial.

Concerning the PAH vasodilator medicines analyzed: 206 patients received phosphodiesterase type 5 inhibitors, like sildenafil (brand name Revatio) and udenafil (brand name Zydena, not approved in U.S.); 132 given the guanylate cyclase stimulator riociguat (brand name Adempas); and 101 patients who were treated with endothelin receptor antagonists, bosentan (brand name Tracleer) and macitentan (brand name Opsumit).

The pooled analysis (called meta-analysis) of outcomes in the two patient groups found that risks in three areas of clinical importance — all-cause mortality, cardiovascular mortality, and worsening heart failure (defined as a higher number of hospitalizations or worsening of lung or peripheral swelling) — tended to be greater in those given PAH medications than in control patients. This difference, however, was not statistically different.

Pulmonary arterial blood pressure and blood flow measurements (assessed by right heart catheterization and echocardiography) tended to be better in patients taking PAH medicines, but such improvement again did not reach statistical significance.

Because patient populations and interventions were considerably different between the clinical trials included in this study, a more detailed analysis grouping patients by type of treatment used or heart failure type was performed. No significant clinical benefits of using vasodilators indicated for PAH were found.

“The current meta-analysis showed that there is insufficient evidence at this stage to suggest clinical benefits from these agents for PH-LHD, despite their prevalent off-label usage,” the researchers wrote. Rather, on the basis of the observed trend for an increased risk of mortality and a worsening of heart failure, “these agents should not be prescribed in this setting, unless further evidence of benefit arises in the future.”

PH News

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